# NM_012203.2(GRHPR):c.626C>T (p.Ser209Phe)

https://sugi.bio/variant/grhpr-p-ser209phe

## Summary

**GRHPR p.Ser209Phe (c.626C>T)** is classified **Pathogenic/Likely pathogenic** in GRHPR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.9815); Ultra-rare (popmax 0.016%, afr); Associated with primary hyperoxaluria type 2.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs375014308 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.016%, afr)

## For patients & families {#patients}

This is a change in the GRHPR gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to primary hyperoxaluria type 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Germany) |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GRHPR is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Primary hyperoxaluria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperoxaluria — Very frequent (99-80%)
- Calcium oxalate nephrolithiasis — Very frequent (99-80%)
- Nephrocalcinosis — Frequent (79-30%)
- Abnormality of the dentition — Frequent (79-30%)
- Retinopathy — Frequent (79-30%)
- Optic disc pallor — Frequent (79-30%)
- Optic atrophy — Frequent (79-30%)
- Hematuria — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002836/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GRHPR](https://sugi.bio/atlas/gene/GRHPR/) |
| Protein change (HGVS p.) | p.Ser209Phe |
| Coding change (HGVS c.) | c.626C>T |
| MANE Select transcript | [NM_012203](https://www.ncbi.nlm.nih.gov/nuccore/NM_012203) |
| dbSNP | [rs375014308](https://www.ncbi.nlm.nih.gov/snp/rs375014308/) |
| Variant type | single nucleotide variant |
| Location | chr9:37430538-37430538 (GRCh38) |
| ClinVar | [VCV2067052](https://www.ncbi.nlm.nih.gov/clinvar/variation/2067052/) |

**All HGVS expressions:** `NC_000009.11:g.37430535C>T`, `NC_000009.12:g.37430538C>T`, `NG_008135.1:g.12829C>T`, `NM_012203.1:c.626C>T`, `NM_012203.2:c.626C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9815) — concordant with the pathogenic call
- REVEL 0.887 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.158 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 4.887, GERP 1.84, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in GRHPR (of 1,921 modeled).
- CADD: **PHRED 27.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.87** across the covering region of the MANE Select transcript (37,422,751–37,436,779), spanning 14,028 bp. Chi-square p 0.0084. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.016%** (afr) · FAF95 0.00921% · FAF99 0.00722% · 12/74,926 in the highest group · 12/1,613,754 alleles overall — ultra-rare (popmax 0.016%, afr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GRHPR** population constraint: LOEUF 1.313, pLI 3.7191e-09, missense-Z 0.86189; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.80, 98% of residues very-high.

**4 experimental structure(s)** (PDB): [2GCG](https://www.rcsb.org/structure/2GCG), [2H1S](https://www.rcsb.org/structure/2H1S), [2Q50](https://www.rcsb.org/structure/2Q50), [2WWR](https://www.rcsb.org/structure/2WWR).

## What this gene does {#gene-function}

*Describes the biological roles of GRHPR (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GRHPR's established molecular role includes hydroxypyruvate reductase (NADH) activity.


### Pathways affected {#pathways}

GRHPR participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glyoxylate metabolism and glycine degradation](https://reactome.org/content/detail/R-HSA-389661) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** hydroxypyruvate reductase (NADH) activity, hydroxypyruvate reductase [NAD(P)H] activity, glyoxylate reductase (NADPH) activity, protein homodimerization activity, NADPH binding.

**Biological process:** glyoxylate metabolic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-06.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-05 |
| Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-27 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-25 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-11-06 |

## Associated conditions {#conditions}

[primary hyperoxaluria type 2](https://sugi.bio/atlas/disease/primary-hyperoxaluria-type-2/).

**Reported phenotype names (ClinVar):** Primary hyperoxaluria, type II, not provided, none provided, OXALOSIS II, Primary hyperoxaluria type 2, D-GLYCERATE DEHYDROGENASE DEFICIENCY, GLYCERIC ACIDURIA, GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE DEFICIENCY.

## Similar variants {#similar}

Related GRHPR variant pages (same residue, condition, or type): [GRHPR c.404+5G>A](/variant/grhpr-c-404-plus-5g-a), [GRHPR c.493+2T>A](/variant/grhpr-c-493-plus-2t-a), [GRHPR c.494-2A>G](/variant/grhpr-c-494-minus-2a-g), [GRHPR c.734+1G>A](/variant/grhpr-c-734-plus-1g-a), [GRHPR c.735-1G>A](/variant/grhpr-c-735-minus-1g-a), [GRHPR c.83+1G>C](/variant/grhpr-c-83-plus-1g-c), [GRHPR c.84-2A>G](/variant/grhpr-c-84-minus-2a-g), [GRHPR c.865+1G>A](/variant/grhpr-c-865-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2067052). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*